The present invention relates to novel substituted cyclohexylamines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are both dopaminergic and serotonergic agents.
Compounds which interact with the dopamine D2 (DA D2) receptor have been shown to be efficacious in the treatment of psychiatric disorders such as schizophrenia. However, chronic administration of these agents causes various movement disorders both clinically and in animal models. It has been shown that administration of compounds that interact with the serotonin-1A (5-HT1A) receptor can block or prevent these extrapyramidal side effects in preclinical models (Neal-Beliveau B. S., et al., J. Pharm. Exp. Ther., 1993;265:207-17). Increases in both dopamine D2 and 5-HT1A receptor densities have been observed during postmortem studies of schizophrenic brains (Hashimoto T., et al., Life Sciences, 1991;48:355-363 and references cited therein). Thus, it seems likely both DA D2 and 5-HT1A receptors play an important role in the etiology of schizophrenia. Taken together, these studies suggest that compounds having the ability to interact with both dopamine D2 and 5-HT1A receptors will have increased efficacy in the treatment of schizophrenia while causing less side effects. The compounds of the present invention have potent binding affinity for both the dopamine D2 receptor and the 5-HT1A receptor. They also show activity in a behavioral paradigm predictive of antipsychotic efficacy.
A series of substituted cyclohexanols and cyclohexylamines represented by the formula ##STR1## wherein R is --OR.sup.3, wherein R.sup.3 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl lower alkyl, lower alkanoyl, aroyl, or aryl lower alkanoyl; ##STR2## wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl, lower alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, aryl lower alkanoyl, heteroaryl lower alkanoyl, aroyl, heteroaroyl, or R.sup.4 and R.sup.5 are taken together with the nitrogen atom to which they are attached to form a ring denoted by ##STR3## wherein p is zero or an integer from 1 to 4 and R.sup.6 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl ##STR4## wherein X is oxygen or sulfur or ##STR5## wherein R.sup.6 is as defined above, or ##STR6## wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aryl lower alkyl, lower alkanoyl, aryl lower alkanoyl, aroyl, or R.sup.4 and R.sup.5 are taken together with the oxygen and nitrogen atoms to which they are attached to form a ring denoted by ##STR7## wherein q is an integer from 2 to 3 and R.sup.6 is as defined above;
m is zero or an integer from 1 to 2; PA1 R.sup.1 is hydrogen, aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower akyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl or halogen; PA1 n is zero or an integer from 1 to 4; PA1 R.sup.2 is ##STR8## wherein R.sup.7 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl or halogen; PA1 and the corresponding cis and trans isomers thereof; or a pharmaceutically acceptable acid addition salt thereof are disclosed in U.S. Pat. No. 5,047,406 as dopaminergic agents useful as antipsychotic and antihypertensive agents as well as for treating hyperprolactinaemia-related conditions and central nervous system disorders. PA1 n is an integer from 1 to 2; PA1 R.sup.2 is ##STR11## wherein R.sup.3 is 2-pyrimidinyl, 2-pyrimidinyl substituted by 1 to 2 substituents selected from the group consisting of PA1 R is 2-, 3-, or 4-pyridinyl, PA1 R.sup.1 is hydrogen or methyl; PA1 n is an integer of 2; PA1 R.sup.2 is ##STR12## wherein R.sup.3 is 2-pyrimidinyl, 2-, 3-, or 4-pyridinyl, PA1 R is 2-, 3-, or 4-pyridinyl, PA1 R.sup.1 is hydrogen or methyl; PA1 n is an integer of 2; PA1 R.sup.2 is ##STR13## wherein R.sup.3 is 2-pyrimidinyl, 2-, 3-, or 4-pyridinyl, PA1 R is 2-quinazolinyl, or PA1 cis-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl -amine hydrochloride; PA1 trans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)ethyl]-cyclohexyl}-pyrimidin-2-y l-amine; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-ami ne; PA1 trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyr imidin-2-yl-amine; PA1 trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-met hyl-pyrimidin-2-yl-amine; PA1 trans-(4-{2-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyr imidin-2-yl-amine; PA1 trans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)ethyl]-cyclohexyl}-quinazolin-4- yl-amine; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-am ine; PA1 cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amin e; PA1 cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine hydrochloride; PA1 trans-Methyl-{4-[2-(4-phenyl-piperazin-1-yl)ethyl]-cyclohexyl}-pyrimidin-2- yl-amine; PA1 trans-(5-Fluoro-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cycl ohexyl}-amine; PA1 trans-Pyrimidin-2-yl-(4-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-et hyl}-cyclohexyl)-amine; PA1 trans-(4-{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimi din-2-yl-amine; PA1 trans-Pyrimidin-2-yl-{4-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-cyclohe xyl}-amine; PA1 trans-(4-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimid in-2-yl-amine; PA1 trans-{4-[2-(4-Phenyl-3,6-dihydro-2H-pyridin-1-yl)-ethyl]-cyclohexyl)}-pyri midin-2-yl-amine; PA1 trans-Pyrimidin-2-yl-{4-[2-(4-thiazol-2-yl-piperazin-1-yl)-ethyl]-cyclohexy l}-amine; PA1 trans-(4-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimi din-2-yl-amine; PA1 trans-Pyrimidin-2-yl-{4-[2-(2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)-ethy l]-cycohexyl}-amine; PA1 trans-{4-[2-(4-Pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2- yl-amine; PA1 trans-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-cyclohexyl}-pyrimidin- 2-yl-amine; PA1 trans-4-(4-{2-[4-(Pyrimidin-2-ylamino)-cyclohexyl]-ethyl}-piperazin-1-yl)-p henol; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-3-yl-amine ; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-2-yl-amine ; PA1 trans-(4-Methyl-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cycl ohexyl}-amine; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-thiazol-2-yl-amine ; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrazin-2-yl-amine ; PA1 trans-Benzothiazol-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}- amine; PA1 cis-(1-Methyl-1H-benzoimidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl] -cyclohexyl}-amine; PA1 trans-(1-Methyl-1H-benzoimidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethy l]-cyclohexyl}-amine; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-4-yl-ami ne; PA1 trans-(3-Methyl-pyridin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cycloh exyl}-amine; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-4-yl-amine ; PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-trifluoromethyl- pyrimidin-2-yl)-amine; PA1 trans-(5-Methoxy-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyl ohexyl}-amine; PA1 trans-(5-Methyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclo hexyl}-amine; PA1 trans-(5-Phenyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclo hexyl}-amine; and PA1 trans-(4,6-Dimethyl-pyrimidin-2-yl-{4-[2-(4phenyl-piperazin-1-yl)-ethyl]-cy clohexyl}-amine; or a pharmaceutically acceptable acid addition salt thereof. PA1 trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-ami ne; or a pharmaceutically acceptable acid addition salt thereof. PA1 n is an integer from 1 to 2; PA1 R.sup.2 is ##STR15## wherein R.sup.3 is 2-pyrimidinyl, 2-pyrimidinyl substituted by 1 to 2 substituents selected from the group consisting of
A series of 2-(4-phenyl-1-piperazinyl-alkyl)-aminopyrimidine derivatives represented by the formula ##STR9## wherein R.sup.1 and R.sup.3 may be the same or different and independently represent hydrogen, halogen, an amino group, a hydroxyl group, a straight or branched chain lower alkyl group, a straight or branched chain lower alkoxy group, or a straight or branched chain hydroxy-lower alkyl group, R.sup.2 represents hydrogen, halogen, a carboxyl group, a straight or branched chain lower alkyl group, a straight or branched chain lower alkylcarbonyl group, or a straight or branched chain lower alkyloxycarbonyl group, R.sup.4 and R.sup.5 may be the same or different and independently represent hydrogen, halogen, a straight or branched chain lower alkyl group, or a straight or branched chain lower alkoxy group, and n represents an integer of 2 to 6 or a pharmaceutically acceptable acid addition salt thereof are disclosed in U.S. Pat. No. 5,075,308 as therapeutic agents for urinary obstruction.
The compounds of the present invention, unlike the compounds disclosed in U.S. Pat. No. 5,047,406, interact with both the dopamine D2 and serotonergic 1A receptors. Thus, the compounds of the present invention are useful in the treatment of psychoses such as schizophrenia without the adverse extrapyramidal effects associated with an agent that interacts only with the dopamine receptor.